Abstract
Emerging evidence has shown that active enhancers are abundantly transcribed, generating long non-coding RNAs, called enhancer RNAs (eRNAs). While putative eRNAs are often observed from RNA sequencing, the roles of most eRNAs remain largely unknown. Previously, we identified putative enhancer regions at the MALAT1 locus that form chromatin-chromatin interactions under hypoxia, and one of these enhancers is located about 30 kb downstream of the NEAT1 gene and -20 kb upstream of the MALAT1 gene (MALAT1-20 kb enhancer). Here, we report that a novel eRNA, named eRNA of the NEAT1-MALAT1-Locus (eNEMAL), is transcribed from the MALAT1-20 kb enhancer and conserved in primates. We found that eNEMAL is upregulated in response to hypoxia in multiple breast cancer cell lines, but not in non-tumorigenic MCF10A cells. Overexpression and knockdown of eNEMAL revealed that alteration of eNEMAL level does not affect MALAT1 expression. Instead, we found that eNEMAL upregulates the long isoform of NEAT1 (NEAT1_2) without increasing the total NEAT1 transcript level in MCF7 breast cancer cells, suggesting that eNEMAL has a repressive effect on the 3'-end polyadenylation process required for generating the short isoform of NEAT1 (NEAT1_1). Altogether, we demonstrated that an eRNA transcribed from a MALAT1 enhancer regulates NEAT1 isoform expression, implicating the MALAT1-20 kb enhancer and its transcript eNEMAL in co-regulation of MALAT1 and NEAT1 in response to hypoxia in breast cancer cells.
Highlights
Most described somatic mutations in cancer are found in noncoding regions of the genome and are often contained within regulatory regions such as enhancers [1], implicating dysregulation of enhancer functions in human diseases
Enhancer RNAs is recognized as a sign of active enhancers [14,15,16], we examined whether one or more of the Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) enhancers we previously identified in the MALAT1 locus (-20 kb enhancer, -7 kb enhancer, and 3’ enhancer) [13] may encode enhancer RNAs (eRNAs) which would be upregulated in response to hypoxia
cap analysis of gene expression (CAGE) supported transcription initiating on the minus strand approximately -20.3 kb upstream of the MALAT1 transcription start site, which overlapped with other epigenetic marks consistent with enhancer elements (Fig 1B)
Summary
Most described somatic mutations in cancer are found in noncoding regions of the genome and are often contained within regulatory regions such as enhancers [1], implicating dysregulation of enhancer functions in human diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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